Arrhythmias and cardiac dysfunction occur when sympathetic neural influences are excessive. Recent evidence indicates that structural remodeling of cardiac nerves contributes to hyperexcitability. Because nerve growth factor (NGF) is the major protein regulating sympathetic innervation, it is implicated in sympathetic neuroplasticity. In the present application we test the hypothesis that abnormal NGF synthesis after myocardial infarction leads to cardiac sympathetic nerve remodeling. We propose that abnormally high NGF expression in peri-infarct inflammatory myofibroblasts and macrophages contributes to hyperinnervation, and that deficient NGF expression in parasympathetic neurons leads to loss of parasympathetic presynaptic inhibition of sympathetic nerves. The long-term goals of this study are to understand the molecular mechanisms that regulate cardiac sympathetic innervation and to devise interventional strategies to correct abnormal innervation patterns. Experiments in Aim 1 demonstrate that coronary artery ligation in rats upregulates NGF in specific subsets of inflammatory cells. Aim 2 explores temporo-spatial features of ingrowth of identified axons and assesses the role of trophic factors in this process. Aim 3 investigates if sympathetic innervation itself promotes inflammatory cell NGF expression via beta adrenergic receptors. In Aim 4 we assess whether NGF expression in cardiac parasympathetic neurons, which may govern formation of axo-axonal inhibitory synapses, is regulated by sympathetic innervation. In Aim 5 we examine the role of adrenergic receptors in regulating cardiac parasympathetic NGF synthesis. Aim 6 investigates the possibility that adrenergic receptor down-regulation leads to diminished cardiac parasympathetic NGF synthesis in heart failure. Aim 7 investigates whether reduced parasympathetic NGF can account for diminished axo-axonal inhibition in heart failure. We use morphometric histochemistry, cell and tissue culture, protein and mRNA assays, and in vivo recordings to attain these goals. These studies will provide new and important information on molecular mechanisms regulating sympathetic neuroplasticity within the damaged heart, thus providing a more complete understanding of post-infarct cardiac dysfunction. Importantly, they will provide novel data on how trophic factor synthesis is regulated by adrenergic receptors, and may serve as a basis for pharmacological interventions aimed at preventing or reversing deleterious cardiac sympathetic remodeling.